Poxviruses have evolved multiple mechanisms to modulate and evade host immunity. The orthopoxvirus, vaccinia virus is used as a vaccine to induce protective immunity and prevent smallpox transmission. Immunization with vaccinia virus can promote immunity in humans, yet concerns have been raised as to vaccine effectiveness and safety, particularly for individuals with immunodeficiencies and hypersensitivities. Eludicating novel mechanisms of poxvirus immune evasion, therefore remains an important priority with regards to developing improved vaccines. Project 1tests the hypothesis that vaccinia virus disrupts the function of MHC class II molecules, thus compromising full activation of host immune responses. A transient decrease in T cell responsiveness linked to defects in antigen presenting cells, has been reported in humans following vaccinia virus immunization. Our studies demonstrate vaccinia virus infection of antigen presenting cells selectively disrupts MHC class ll-restricted antigen presentation to T cells. The long-term goals of this project are to understand mechanistically how vaccinia virus perturbs class II antigen presentation, and how virus-induced changes in antigen presenting cells influence the development of virus-specific CD4 T cells. Thus, aim 1 of the resubmitted proposal will test whether vaccinia virus infection of antigen presenting cells selectively disrupts the formation and longevity of peptide-MHC class II complexes. A second aim is to determine whether vaccinia-encoded molecules influence class II function, trafficking, as well as antigen processing. Natural poxvirus transmission frequently occurs via delivery into the lungs, thus the effects of in vivo viral infection on class II presentation in the lung will be examined in aim 3. Whether induced allergic inflammation in the lung, influences viral disruption of class II presentation, will be addressed. Together, these studies will provide key insights into the mechanisms used by vaccinia virus to subvert class II presentation and T cell activation. RELEVANCE (See instructions): Class II presentation is a key function of antigen presenting cells, linking Project 1with others in the program designed to study the effects of poxvirus infection on antigen presenting cells and viral immunity. The results obtained in this project will be relevant for devising novel strategies to overcome the inhibitory effects of vaccinia virus, with implications for enhancing protective immunity to related viruses such as smallpox.